A New Simplified Protocol for Copper(I) Alkyne-Azide Cycloaddition Reactions Using Low Substoichiometric Amounts of Copper(II) Precatalysts in Methanol

Article abstract of DOI:10.1055/s-0035-1560526

Copper(II) carboxylates are reduced efficiently by methanol in the presence of alkynes and form yellow alkynylcopper(I) polymeric precatalysts that are involved with azides, in the absence of added ligands, in the catalytic cycles that result in the forma

Full text of DOI:10.1055/s-0035-1560526

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 51–56
letter
51
B. R. Buckley et al.
Letter
Synlett
A New Simplified Protocol for Copper(I) Alkyne–Azide Cycloaddi-
tion Reactions Using Low Substoichiometric Amounts of Cop-
per(II) Precatalysts in Methanol
Benjamin R. Buckley
Maria M. P. Figueres
Amna N. Khan
N
N
N
N
Ar
N
N
Ar
Cu(OAc)2/MeOH
R
Cu
n
R
H
R
Harry Heaney*
Department of Chemistry, Loughborough University, Loughborough,
Leicestershire, LE11 3TU, UK
b.r.buckley@lboro.ac.uk
m.m.pardo-figueres@lboro.ac.uk
amnankhan@gmail.com
h.heaney@lboro.ac.uk
Dedicated to Professor Steven V. Ley FRS for his excellent achievements in organic chemistry on the occasion of his 70th birthday
Received: 25.09.2015
Accepted: 16.10.2015
Published online: 11.11.2015
DOI: 10.1055/s-0035-1560526; Art ID: st-2015-d0767-l
The use of copper(II) acetate in CuAAC reactions has
been studied in considerable detail by Zhu and his co-work-
ers, paying particular attention to reactions involving che-
lating azides as well as other ligands.12 The reduction of a
copper(II) 1,10-phenantholine complex to the related cop-
per(I) complex in propan-2-ol implicated the alcohol as the
reducing agent.13 In an earlier study we established that the
phenylethynylcopper(I) polymer was involved in CuAAC re-
actions by the interaction of phenylacetylene with cop-
per(II) hydroxyacetate in easily oxidisable alcohols, includ-
ing isopropanol.10b The present investigation was undertak-
en for a number of reasons. First, the original protocol,
shown in Scheme 1, involved the addition of a solution of
copper(II) sulfate to a solution of an alkyne and an azide in
a mixture of tert-butanol, water, and a fivefold excess of so-
dium ascorbate. Second, no additional ligands were used.
Third, the acidities of ascorbic acid (pKa ca. 4.1) and acetic
acid (pKa 4.76) are almost identical, and fourth, π complex-
ation of alkynes by metallic ions such as copper(I) reduce
the acidity of alkynes by ca. 10 pKa units.14 The recent re-
port of the use of a copper(II)-tren precatalyst15 in CuAAC
reactions, and the use of copper(I) oxide in the presence of
dioxygen,16 prompts this report of a highly efficient and
simple protocol that uses copper(II) carboxylates in metha-
nol.
Abstract Copper(II) carboxylates are reduced efficiently by methanol
in the presence of alkynes and form yellow alkynylcopper(I) polymeric
precatalysts that are involved with azides, in the absence of added li-
gands, in the catalytic cycles that result in the formation of 1,4-disubsti-
tuted 1,2,3-triazoles.
Key words alkyne, azide, copper(I), cycloaddition, triazole
The disclosure of highly regioselective copper(I)-cata-
lysed intermolecular alkyne–azide cycloaddition (CuAAC)
reactions by Meldal and Sharpless and their co-workers1
has been followed each year by a very large number of re-
ports of the preparation of triazoles that have been used for
a variety of purposes. Click CuAAC reactions have become
perhaps the most widely studied of all copper-catalysed re-
actions.2 The use of sodium ascorbate together with cop-
per(II) sulfate, in aqueous tert-butanol,1c is probably the
most currently used CuAAC protocol.
However, in addition to examples involving the direct
use of copper(I) salts,1a,b,3 there are other ways of generat-
ing the copper(I) state. For example, reactions of metallic
copper together with copper(II) salts provides a method
where the presence of ascorbate or its oxidation product
may have a deleterious effect.4 Other catalyst systems in-
clude a copper nanocluster,5 copper(I) zeolites,6 a copper-
manganese spinel oxide,7 copper(I) oxide ‘on water’,8 and
copper on carbon.9a,b Our previous studies of CuAAC reac-
tions centred on copper(II) precatalysts in the absence of li-
gands, using copper(II) hydroxyacetate,10 and more recently
Gerhardite [copper(II) hydroxynitrate], the copper(II) spe-
cies present in ‘Copper-in-Charcoal’.11
+
N
Bn
N
Bn
N
N
CuSO4·5H2O (1 mol%)
N
N
–
sodium ascorbate (5 mol%)
Ph
91%
O
H2O/t-BuOH (2:1), r.t., 8 h
Ph
O
Scheme 1 The copper(II) sulfate/sodium ascorbate protocol for a
CuAAC reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56

52
B. R. Buckley et al.
Letter
Synlett
N
N
N
N
N
N
Cu(OAc)2·H2O (0.1 mol%)
MeOH (degassed)
Me
CF3
microwave, 100 °C, 20 min
CF3
98%
Me
Scheme 2 The copper(II) acetate/methanol protocol for CuAAC reactions
We observed, at an early stage of the present investiga-
tion, that a solution of phenylacetylene and copper(II) ace-
tate in wet degassed methanol at ambient temperature
gave the yellow polymeric phenylethynylcopper(I),17 in an
almost quantitative yield after ca. two days; similarly, cop-
per(II) formate gave the same product more rapidly. The ab-
sence of the Glaser reaction product, 1,4-diphenylbuta-1,3-
diyne, as shown by GC–MS, confirmed that methanol was
the reducing agent.10c,18 Reactions using copper(II) salts in
solvents such as acetonitrile result in the formation of Gla-
ser products in order to reduce copper(II) salts to the cop-
per(I) precatalyst required to catalyse CuAAC reactions.10a
Our earlier studies of CuAAC reactions10 showed that
arylethynylcopper(I) polymers are efficient precatalysts
that are formed in high yields and that reactions carried out
at ambient temperature, in the absence of added ligands,
were complete after ca. 15 hours.10b CuAAC reactions were
shown to proceed more rapidly in microwave-assisted reac-
tions. Importantly, that alkynylcopper(I) polymers are in-
volved in the catalytic cycle in the absence of ligands was
established by crossover reactions.10a,b,2f For example, in a
reaction of p-tolylethyne with benzylazide using a catalytic
amount of phenylethynylcopper(I), we recovered p-tolyl-
ethynylcopper(I).
1-benzyl-4-phenyl-1,2,3-triazole in 71% yield after three
days: A similar reaction, carried out at 50 °C for 4 hours
gave the same product in 78% yield. Reactions of ben-
zylazide with octa-1,7-diyne or nona-1,8-diyne were also
carried out at 50 °C for 4 hours and gave the expected prod-
ucts in 72% and 69% yields, respectively.19,21 The reaction of
3-trifluoromethylbenzyl azide with phenylacetylene or p-
tolyl-acetylene and copper(II) acetate (1 mol%), at ambient
temperature in degassed methanol, proceeded very slowly
and gave, after 12 hours, the expected triazole derivatives in
only 37% and 51%, respectively. We then carried out a series
of microwave-assisted reactions, using a mixture of p-tolyl-
acetylene and 3-trifluoromethylbenzyl azide together with
amounts of copper(II) acetate, starting with 5 mol%, in or-
der to establish the minimum reasonable amount of the
precatalyst required. Reactions using 0.1 mol% of copper(II)
acetate gave the expected triazole derivative, shown in
Scheme 2, in an almost quantitative yield.23 As our earlier
results had shown that CuAAC reactions can be carried out
at ambient temperatures using preformed alkynylcopper(I)
polymers,10b in the absence of added ligands, the present
results suggest that the reduction of copper(II) to give the
precatalytic copper(I) species, is the slow step in our new
protocol.
We therefore carried out reactions of phenylacetylene
with benzylazide at ambient temperature using 1 mol% of
copper(II) acetate in methanol, in order to establish that
methanol could be used as the reducing agent and obtained
Reactions using other copper(II) carboxylates as precat-
alysts for CuAAC reactions were carried out; but none was
found to be superior to copper(II) acetate.
Table 1 Influence of Copper(II) Salts on the CuAAC Reactiona
F3C
copper salt (0.1 mol%)
degassed MeOH
N3
N
N
+
N
Me
20 min, 100 °C
microwave
Me
F3C
Entry
Copper Salt
Yield (%)b
1
2
3
4
5
6
Cu(HCO2)2·4H2O
Cu(n-C6H11CO2)2
Cu(C6H5CO2)2
Cu(C6H11O7)2
Cu(acac)2
92
78
72
54
52
98
Cu(OAc)2·5H2O
a General conditions: copper salt (0.1 mol%), alkyne (1.5 equiv), azide (1.0 equiv), degassed MeOH, 100 °C, microwave, 20 min.
b Isolated yield after chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56

53
B. R. Buckley et al.
Letter
Synlett
Copper(II) acetylacetonate in methanol did function as a
precatalyst; however, as anticipated, it was poor by com-
parison to the copper(II) carboxylates that we studied. The
results of the trial reactions are shown in Table 1.
The optimum conditions (Table 1, entry 6) were then
applied to a range of alkyne–azide combinations to afford
the corresponding triazoles. In some cases a higher loading
of copper acetate was required to obtain the best yields in
the cycloaddition reactions (Table 2). Although many of the
reactions reported were carried out using degassed metha-
nol; reactions can be carried out in the presence of air since
the reducing agent methanol, like ascorbate in the Sharp-
less protocol,1c is present in a very large excess.
Table 2 Application to a Range of Substratesa
N
N
Cu(OAc)2⋅H2O (x mol%)
degassed MeOH
R2
R1
N
N3
R1
R2
+
100 °C, microwave
Entry
1
Catalyst loading (mol%)
0.1
Time
Product
Yield (%)b
71
N
N
N
CF3
10 min
Ph
N
N
N
CF3
2
3
0.1
0.1
10 min
98
70
Me
N
N
N
CF3
10 min
O
PMP
AcO
AcO
N
N
N
O
4
5
1.0
1.0
20 min
30 min
46
99
N
AcO
Ph
OAc
AcO
AcO
N
O
OPh
N
AcO
OAc
OAc
O
AcO
N
N
N
6
1.0
60 min
92
N
AcO
Ph
OAc
OAc
O
AcO
AcO
N
7
8
1.0
1.0
0.1
0.1
30 min
20 min
20 min
20 min
96
86
65
70
OPh
N
OAc
N
N
N
OMe
Ph
O
N
N
N
9
PhO
BzO
OMe
O
O
N
N
N
10
OMe
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56

54
B. R. Buckley et al.
Letter
Synlett
Table 2 (continued)
Entry
Catalyst loading (mol%)
Time
Product
Yield (%)b
85
Ph
N
N
N
11
0.1
20 min
Me
Ph
N
N
N
N
N
12
13
1.0
1.0
20 min
72 h
72
Ph
Ph
N
71c
Ph
Ph
N
N
N
14
1.0
30 min
65
t-Bu
72d,19
Ph
N
Ph
N
15
16
1.0
1.0
4 h
4 h
N
N
N
N
Ph
69d,21
N
N
Ph
N
N
N
N
N
Ph
Ph
N
N
N
N
+
N
17
0.0
30 min
12e,f
Ph
Ph
a General conditions: Copper salt (0.1 mol%), alkyne (1.5 equiv), azide (1.0 equiv), degassed MeOH, 100 °C, microwave, 20 min.
b Isolated yield after chromatography.
c Conditions: Copper salt (1.0 mol%), alkyne (1.5 equiv), azide (1.0 equiv), MeOH, r.t., 3 d.
d Conditions: Copper salt (1.0 mol%), diyne (2.2 equiv), azide (1.0 equiv), MeOH, conventional heating 50 °C, 4 h.
e Conversion evaluated by 1H NMR spectroscopy by integration of benzylazide CH2 vs. benzyl CH2 in the triazole products.
f Sum of both regioisomers.
In summary, we have shown that a simple protocol can
be used to obtain good to excellent yields of 1,4-disubsti-
tuted 1,2,3-triazoles, that involve alkynylcopper(I) poly-
meric precatalysts in the CuAAC reactions carried out in the
absence of added ligands. Also, that whereas phenyl-
ethynylcopper(I) has been prepared by a number of meth-
ods,17 our present results demonstrate that reactions of
alkynes in methanol in the presence of, for example cop-
per(II) acetate, provides the simplest method of preparing
the alkynylcopper(I) polymers. The new protocol may also
stimulate the use of alkynylcopper(I) compounds as precat-
alysts in a variety of other reactions. In addition to other re-
cent examples,24 alkynylcopper(I) polymers may be in-
volved for example in the flow generation of azides used in
the copper(I)-catalysed preparation of allenes from termi-
nal alkynes.25
Acknowledgment
The authors are grateful to The Higher Education Commission of Paki-
stan for a visiting fellowship (to A.N.K.) and the EU Lifelong Learning
Programme for support (to M.M.P.F), and Loughborough University
for research funding. B.R.B. also thanks Research Councils UK for a
RCUK fellowship.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560526.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56

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B. R. Buckley et al.
Letter
Synlett
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(19) Bistriazole Prepared from 1,7-Octadiyne and Benzyl Azide20
Benzyl azide (0.15 g, 1.1 mmol) and 1,7-octadiyne (0.053 g, 0.5
mmol) were added to a 3 mL vial containing MeOH (2 mL)
which was fitted with a magnetic stirrer bar. Copper(II) acetate
mono-hydrate was added (1 mg, 0.005 mmol, 0.1 mL from a
stock solution in MeOH containing 10 mg/mL), and the vial was
closed. The reaction mixture was then stirred and heated at
50 °C for 4 h on a stirrer hotplate fitted with an aluminium vial
holder and allowed to cool. The colourless precipitate was fil-
tered, washed with cold MeOH (2 × 5 mL), Et2O (5 mL), and
allowed to dry in air to give colourless crystals (0.13 g, 72%); mp
1
156–158 °C. H NMR (400 MHz, CDCl3): δ = 7.35–7.34 (6 H, m),
7.26–7.22 (4 H, m), 7.17 (2H, s), 5.47 (4 H, s), 2.72–2.68 (4 H, m),
1.72–1.69 (4 H, m) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.7,
135.2, 129.3, 128.8, 128.2, 120.9, 54.2, 29.1, 25.7 ppm. HRMS:
m/z calcd for C22H24N6Na [M + Na]: 395.1960; found: 3955.1959.
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(21) Bistriazole Prepared from 1,8-Nonadiyne and Benzyl Azide22
A similar reaction gave colourless crystals (0.13 g, 69%); mp
(7) Yousuf, S. K.; Mukherjee, D.; Singh, B.; Maity, S.; Taneja, S. C.
Green Chem. 2010, 12, 1568.
(8) Wang, K.; Bi, X.; Liao, P.; Fang, Z.; Meng, X.; Zhang, Q.; Liu, Q.; Ji,
Y. Green Chem. 2011, 13, 562.
1
121–123 °C. H NMR (400 MHz, CDCl3): δ = 7.37–7.35 (6 H, m),
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(b) Lee, C.-T.; Huang, S.; Lipshutz, B. H. Adv. Synth. Catal. 2009,
351, 3139.
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Heaney, H. Chem. Eur. J. 2010, 16, 6278. (c) Buckley, B. R.; Dann,
S. E.; Harris, D. P.; Heaney, H.; Stubbs, E. C. Eur. J. Org. Chem.
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7.26–7.22 (4 H, m), 7.17 (2 H, s), 5.48 (4 H, s), 2.67 (4 H, t, J = 9.6
Hz), 1.71–1.60 (4 H, m), 1.40–1.37 (2 H, m) ppm. 13C NMR (100
MHz, CDCl3): δ = 148.9, 135.2, 129.3, 128.8, 128.2, 120.8, 54.2,
29.3, 28.9, 25.8 ppm. HRMS: m/z calcd for C23H26N6Na [M + Na]:
409.2117; found: 409.2113.
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(23) Triazole Prepared from p-Tolylethyne and 3-Trifluorometh-
ylbenzyl Azide (Table 2, Entry 2)
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E. C. ACS Catal. 2015, 5, 793.
3-Trifluoromethylbenzyl azide (0.34 g, 1.7 mmol) and p-tolyl-
ethyne (0.30 g, 2.6 mmol) were added to a microwave tube (5
mL) fitted with a magnetic stirrer bar. Copper (II) acetate mono-
hydrate (3.4 mg, 0.017 mmol) was added and the mixture sus-
pended in MeOH (5 mL). The reaction mixture was then heated
in the microwave apparatus at 100 °C for 20 min and allowed to
cool. The reaction mixture was added to EtOAc (50 mL) and H2O
(50 mL), separated, and the aqueous layer extracted with EtOAc
(2 × 50 mL). The EtOAc layers were evaporated under reduced
pressure to give an off-white solid which after recystallisation
from Et2O gave the product as colourless crystals (0.53g, 98%);
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2179.
mp 128–130 °C. IR: νmax = 3135, 2982, 1665, 1448, 1386 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.74–7.72 (3 H, m), 7.66–7.61 (2
H, m), 7.55–7.48 (2 H, m), 7.25 (2 H, d, J = 7.6 Hz), 5.65 (2 H, s),
2.39 (3 H, s) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.6, 138.2,
135.8, 131.5 (q, J = 32.2 Hz), 131.3, 129.8, 129.6, 127.4, 125.67
(q), 125.62, 124.7 (q, J = 3.7 Hz), 123.5 (q, J = 271.2 Hz), 122.3,
119.6, 119.2, 53.6, 21.4 ppm. HRMS: m/z calcd for C15H24N3F3Na
[M + Na]: 340.1032; found: 340.1040.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56

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Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 51–56